EP0287150B1 - Dérivés de 2-bêta-morpholino androstanes et procédés de préparation - Google Patents

Dérivés de 2-bêta-morpholino androstanes et procédés de préparation Download PDF

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Publication number
EP0287150B1
EP0287150B1 EP88200621A EP88200621A EP0287150B1 EP 0287150 B1 EP0287150 B1 EP 0287150B1 EP 88200621 A EP88200621 A EP 88200621A EP 88200621 A EP88200621 A EP 88200621A EP 0287150 B1 EP0287150 B1 EP 0287150B1
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Prior art keywords
morpholinyl
compounds
androstane
androstan
chcl3
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Expired - Lifetime
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EP88200621A
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German (de)
English (en)
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EP0287150A1 (fr
Inventor
David Samuel Savage
Thomas Sleig
Ian Graig Carlyle
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Organon NV
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Akzo NV
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes

Definitions

  • the present invention is concerned with novel 2 ⁇ -morpholino-androstane derivatives, with processes for their preparation and with compositions comprising such derivatives as the active ingredient.
  • 2 ⁇ -morpholino-androstane derivatives have been disclosed in British Patent 1,138,605. These 2 ⁇ ,16 ⁇ -dimorpholino-androstane derivatives, which are neuromuscular blocking agents, exhibit a low potency.
  • R1 in the above formula may be H or an optionally substituted acyl group having 1-12 carbon atoms.
  • Suitable acyl groups are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, 2-carboxyethanoyl, cyclohexanecarbonyl, glycoloyl, trimethylacetyl, phenylpropionyl, propenoyl, 3-butenoyl, 4-pentenoyl, 3-hydroxy-propionyl and 4-hydroxy-butyryl.
  • R1 is an acyl group preference is given to saturated acyl groups having 1-6 carbon atoms which may be substituted by a carboxy and/or a hydroxy group. The most preferred group for R1 is H.
  • R2 in the above formula may be H or an acyl group having 1-12 carbon atoms. Suitable acyl groups are the unsubstituted acyl groups mentioned above. Preferably R2 is a saturated acyl group having 1-6 carbon atoms.
  • R3 in the above formula may be C, N-CH3 or a direct bond.
  • the compounds according to the present invention have a piperidino, a pyrrolidino or a 4 ⁇ -methyl-piperazino group at position 16 ⁇ .
  • this group is piperidino or pyrrolidino.
  • the quaternary ammonium salts of the compounds according to the above formula also form part of the compounds according to the present invention, as do the acid addition salts of the non- and mono-quaternary ammonium compounds.
  • the quaternary ammonium compounds may be 2 ⁇ -quaternary-, 16 ⁇ -quaternary- or 2 ⁇ ,16 ⁇ -bis-quaternary ammonium compounds if the group at 16 ⁇ is piperidino or pyrrolidino; or, in case the group at 16 ⁇ is 4 ⁇ -methylpiperazino, 2 ⁇ ,4 ⁇ -bis-quaternary or 4 ⁇ -mono-quaternary compounds.
  • 16 ⁇ -mono-quaternary ammonium compounds having a piperidino or pyrrolidino group at position 16 ⁇ Preference is given to the 16 ⁇ -mono-quaternary ammonium compounds having a piperidino or pyrrolidino group at position 16 ⁇ . A special preference is given to those 16 ⁇ -mono-quaternary ammonium compounds which have a 3 ⁇ -OH group, since these compounds are stable in solution.
  • the quaternising group in the quaternary ammonium derivatives is an aliphatic hydrocarbon group having 1-6 carbon atoms, such as methyl, ethyl, ethynyl, propyl, allyl, propargyl, butyl, isobutyl, pentyl, cyclopropyl, cyclopropylmethyl and cyclohexyl.
  • the anion in the quaternary ammonium derivatives may in principle be any pharmaceutically acceptable organic or inorganic anion, such as methylsulphonate, p-toluene sulphonate, Cl ⁇ , Br ⁇ or I ⁇ , and is preferably Br ⁇ .
  • the non-quaternised and mono-quaternised compounds may be converted into the acid addition salt thereof, derived from any pharmaceutically acceptable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, hydro-iodic acid, nitric acid, sulphuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, caproic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, tartaric acid, malic acid, pyruvic acid, lactic acid and citric acid.
  • any pharmaceutically acceptable organic or inorganic acid such as hydrochloric acid, hydrobromic acid, hydro-iodic acid, nitric acid, sulphuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, caproic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, tartaric acid, malic acid, pyruvic acid, lactic acid and cit
  • the compounds according to the invention can be prepared by methods employing steps known or obvious to those skilled in the art.
  • the process for the preparation of the compounds according to claim 1 is characterized in that a compound having the formula: wherein R3 has the same meaning as already indicated, is reacted with morpholine, that subsequently, if desired, the compound obtained is acylated and/or quaternised by methods obvious to those skilled in the art and that the non- and mono-quaternary ammonium compounds obtained are converted, if desired, into the acid addition salts thereof.
  • Compounds according to the present invention may be prepared by reacting a compound having the above formula 2 with morpholine.
  • This reaction is carried out at an elevated temperature, usually between 70 and 250 °C, if necessary under pressure and in the presence of water.
  • the reaction time generally will be between 1 and 5 days.
  • the compounds obtained by conducting this reaction are compounds according to the present invention with R1 and R2 both being H, which compounds may be acylated (R1 and/or R2 being an acyl group as discussed above).
  • the acylation reactions are carried out by reaction with an acyl halide at a temperature of 5-60 °C and preferably at room temperature in an organic solvent, like dichloromethane, for 5-48 hours, preferably for 10-30 hours. If acylation of the 17 ⁇ -OH group is desired only, the amount of acylhalide to be used should be more or less equimolar. If the acylation of both the 17 ⁇ -OH and the 3 ⁇ -OH group is desired a molar excess of at least 3:1 of the acyl halide is required.
  • the steroid is reacted with an acyl halide in a molar excess of at least 3:1 (acyl halide:steroid) and subsequently with an alcohol, like methanol, in order to remove the acyl group from the 17 ⁇ -OH group.
  • an alcohol like methanol
  • another acyl group may be incorporated at the 17 ⁇ -OH group in order to prepare compounds according to the present invention having different acyl groups R1 and R2.
  • Another way to produce compounds having different acyl groups R1 and R2 is reacting the non-acylated steroid in equimolar amount with an acyl halide and subsequently with an acid anhydride, like succinic anhydride.
  • the quaternary ammonium compounds are obtained by allowing the 2 ⁇ -morpholino,16 ⁇ -pyrrolidino/piperidino/4 ⁇ -methyl-piperazino compounds to react with an excess of an aliphatic hydrocarbon halide having 1-6 carbon atoms in a suitable solvent, such as methylene chloride, for several days at room temperature or for several hours at elevated temperature.
  • a suitable solvent such as methylene chloride
  • the mono-quaternary compounds can be obtained by reacting the 2 ⁇ -morpholino,16 ⁇ -pyrrolidino/piperidino/4 ⁇ -methyl-piperazino compounds with a restricted amount of hydrocarbon halide while reducing the reaction time, and separating the 2 ⁇ -mono-quaternary and/or the 16 ⁇ -mono-quaternary/4 ⁇ -mono-quaternary compound from the reaction mixture, e.g. by chromatography or by fractional crystallisation. Also use can be made of the fact that the 16 ⁇ -monoquaternary compound is sparingly soluble in certain solvents, e.g. ether.
  • the reaction can then be performed in the presence of such solvent so that the 16 ⁇ -mono-quaternary compound precipitates during the reaction or after the reaction the 16 ⁇ -mono-quaternary compound is precipitated from the reaction mixture by the addition of such solvent.
  • the 2 ⁇ -mono-quaternary compound can be obtained from the mother liquor by e.g. chromatography on alumina.
  • non-quaternary and mono-quaternary compounds can be converted into the acid addition salts thereof in the usual way by reaction with an pharmaceutically acceptable organic or inorganic acid e.g. in aqueous solution.
  • the present invention further relates to compositions comprising at least one of the compounds according to the present invention as the active ingredient.
  • compositions comprising at least one of the compounds according to the present invention as the active ingredient.
  • Such compositions comprise the usual ingredients for compositions having neuromuscular activity.
  • Such compositions are made by methods known in the art.
  • the present compounds are intended particularly for use in clinical practice to produce skeletal muscular paralysis during surgical operations.
  • the compounds are usually administered by intravenous injection, in initial dosages between 5 and 50 mg (bolus injection), followed if necessary by smaller supplementary dosages.
  • Acetyl chloride (10.0 ml) was added to a stirred suspension of (2 ⁇ ,3 ⁇ ,5 ⁇ ,16 ⁇ ,17 ⁇ )-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol (10.0 g) in dichloromethane (100 ml). After 24 h. at room temperature, saturated potassium bicarbonate solution (approx.
  • Acetyl chloride (9.63 ml) was added to a solution of (2 ⁇ ,3 ⁇ ,5 ⁇ ,16 ⁇ ,17 ⁇ )-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol (53.5 g) in dichloromethane (2.14 l) and the reaction was set aside at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (500 ml).
  • Butanoyl chloride (2.2 ml) was added to a solution of (2 ⁇ ,3 ⁇ ,5 ⁇ ,16 ⁇ ,17 ⁇ )-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol 3-acetate (4.3 g) in dichloromethane (43 ml) and the solution was set aside at room temperature for 40 h. The solution was evaporated to dryness under reduced pressure to give a gum, which was taken up in dichloromethane (40 ml).
  • Bromomethane (3.75 g) was added to a solution of (2 ⁇ ,3 ⁇ ,5 ⁇ ,16 ⁇ ,17 ⁇ )-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol diacetate (2.5 g) in dichloromethane (50 ml). The solution was sealed in a pressure bottle and set aside at room temperature for 20 h. The solvent was removed under reduced pressure with the minimum of heating to afford an off-white solid, which was dissolved in acetone (15 ml).
  • Bromoethane (20 ml) was added to a solution of (2 ⁇ ,3 ⁇ ,5 ⁇ ,16 ⁇ ,17 ⁇ )-2-(4-morpholinyl)-16-1-piperidinyl)-androstane-3,17-diol diacetate (2.5 g) in acetonitrile (25 ml) and the mixture was heated in an autoclave at 95 °C for 16 h. The resulting brown solution was evaporated to dryness under reduced pressure to give a gum (2.85 g), which was dissolved in the minimum of dichloromethane (15 ml).
  • Propanoyl chloride (5.24 ml) was added to a solution of 1-[(2 ⁇ ,3 ⁇ ,5 ⁇ ,16 ⁇ ,17 ⁇ )-3-hydroxy-2-(4-morpholinyl)-17-(1-oxopropoxy)-androstan-16-yl]-1-methylpiperidinium bromide (2.62 g) in dichloro-methane (33 ml) and the solution was set aside at room temperature for 20 h.
  • the compounds obtained in Examples 15 and 34 are 5-times more potent than the corresponding 16 ⁇ -morpholino compounds.
  • the potency was tested by measuring the amount of compound necessary for obtaining a 50% reduction of the muscle tension in the Tibialis muscle in the cat.

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  • Chemical & Material Sciences (AREA)
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Claims (7)

  1. Procédé pour la préparation des composés de la formule :
    Figure imgb0059
     dans laquelle
    R₁   est H ou un groupe acyle facultativement substitué ayant 1 à 12 atomes de carbone ;
    R₂   est H ou un groupe acyle ayant 1 à 12 atomes de carbone ; et
    R₃   est C, N-CH₃ ou une liaison directe ;
    et de leurs sels de mono- ou bis-ammonium quaternaire et des sels d'addition d'acides des composés non-quaternaires ou des sels de mono-ammonium quaternaire, caractérisé par le fait qu'un composé répondant à la formule :
    Figure imgb0060
     dans laquelle R₃ a la signification donnée précédemment, est amené à réagir avec la morpholine, puis, facultativement, le composé obtenu est acylé et/ou quaternisé par des méthodes évidentes pour l'homme de l'art, et les composés non-quaternaires ou les sels de mono-ammonium quaternaire obtenus sont facultativement convertis en leurs sels d'addition d'acides.
  2. Procédé selon la revendication 1, caractérisé par le fait que R₁ est H.
  3. Procédé selon la revendication 1 ou 2, caractérisé par le fait que les composés sont des sels de 16β-mono-ammonium quaternaire.
  4. Procédé selon les revendications 1 à 3, caractérisé par le fait que R₂ est un groupe acyle saturé ayant 1 à 6 atomes de carbone.
  5. Procédé selon les revendications 1 à 4, caractérisé par le fait que R₃ est C ou une liaison directe.
EP88200621A 1987-04-14 1988-04-05 Dérivés de 2-bêta-morpholino androstanes et procédés de préparation Expired - Lifetime EP0287150B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88200621T ATE79631T1 (de) 1987-04-14 1988-04-05 2-beta-morpholino-androstanderivate und verfahren zu ihrer herstellung.

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GB8708886 1987-04-14
GB878708886A GB8708886D0 (en) 1987-04-14 1987-04-14 2beta-morpholino-androstane derivatives

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EP0287150A1 EP0287150A1 (fr) 1988-10-19
EP0287150B1 true EP0287150B1 (fr) 1992-08-19

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US (1) US4894369A (fr)
EP (1) EP0287150B1 (fr)
JP (1) JPH0753751B2 (fr)
KR (2) KR0130208B1 (fr)
AT (1) ATE79631T1 (fr)
AU (1) AU608313B2 (fr)
CA (1) CA1291117C (fr)
DE (2) DE3873803T2 (fr)
DK (1) DK174743B1 (fr)
ES (1) ES2043781T3 (fr)
FI (1) FI89057C (fr)
GB (1) GB8708886D0 (fr)
GR (1) GR3006275T3 (fr)
HU (1) HU198738B (fr)
IE (1) IE63672B1 (fr)
NL (1) NL940010I2 (fr)
NZ (1) NZ224228A (fr)
PT (1) PT87250B (fr)
ZA (1) ZA882481B (fr)

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US7642246B2 (en) 2005-09-13 2010-01-05 Sicor Inc. Pure rocuronium bromide

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GB8709565D0 (en) * 1987-04-23 1987-05-28 Akzo Nv 2beta,16beta-diaminoandrostanes
HU210076B (en) * 1992-11-02 1995-01-30 Tuba Process for producing androstane derivatives substituted with quaternisaeted amino group in 16-position and for producing pharmaceutical compositions containing them
GB9302455D0 (en) * 1993-02-08 1993-03-24 Lab Inpharm N V Process for preparing a pharmaceutical preparation having neuromuscular blocking activity
CZ300694A3 (en) * 1993-12-02 1996-05-15 Akzo Nobel Nv Substituted 2beta-morpholinandrostane derivatives, process of their preparation, their use for preparing pharmaceutical preparations and pharmaceutical compositions containing thereof
IT1277700B1 (it) * 1995-12-22 1997-11-11 Poli Ind Chimica Spa Processo di preparazione di 2-beta, 16-beta-diamino 3-alfa, 17-beta- diacilossi 5-alfaandrostani, bloccanti neuromuscolari a struttura
AU2003217676B2 (en) 2002-02-22 2009-06-11 Takeda Pharmaceutical Company Limited Active agent delivery systems and methods for protecting and administering active agents
DE112005000178T5 (de) * 2004-01-15 2007-01-25 Chemagis Ltd. Verfahren zur Herstellung von Rocuroniumbromid und Zwischenprodukte davon
US20060058275A1 (en) * 2004-07-15 2006-03-16 Oded Friedman Processes for preparing stabilized, highly pure rocuronium bromide
US20060058276A1 (en) * 2004-07-15 2006-03-16 Oded Friedman Processes for the preparation and purification of rocuronium bromide
US20060009485A1 (en) * 2005-06-23 2006-01-12 Chemagis Ltd Method of reprocessing quaternary ammonium-containing neuromuscular blocking agents
GB2445746A (en) * 2007-01-17 2008-07-23 Texcontor Ets Use of carbonated water as a solvent for freeze drying, and method of purification comprising dissolution of material in carbonated water and freeze drying
CN101125878B (zh) * 2007-09-30 2011-01-12 浙江仙琚制药股份有限公司 甾体类肌松药物罗库溴铵的制备方法
CN101863948B (zh) * 2009-04-17 2013-07-24 重庆医药工业研究院有限责任公司 高纯度(2β,3α,5α,16β,17β)-2-(4-吗啉基)-16-(1-吡咯烷基)-雄甾烷-3,17-二醇或其组合物及其制备方法
CN101824066B (zh) * 2010-04-08 2012-06-13 浙江仙琚制药股份有限公司 制备罗库溴铵中间体化合物结晶物的方法
ES2593502T3 (es) * 2011-01-26 2016-12-09 Zhejiang Huahai Pharmaceutical Co., Ltd Método de preparación de rocuronio
WO2012145888A1 (fr) 2011-04-25 2012-11-01 浙江华海药业股份有限公司 Procédé de purification du bromure de rocuronium
CA2914154C (fr) 2013-07-01 2021-05-25 Maruishi Pharmaceutical Co., Ltd. Preparation de rocuronium avec une douleur vasculaire amelioree, procede pour la produire et procede pour reduire et soulager la douleur vasculaire l'employant
CN105566433A (zh) * 2016-01-15 2016-05-11 安徽悦康凯悦制药有限公司 一种罗库溴铵的生产工艺
CN108570090B (zh) * 2018-05-25 2021-02-02 江苏盈科生物制药有限公司 一种高纯度罗库溴铵的制备方法
CN110734468B (zh) 2018-07-20 2021-04-16 济南高德医药科技有限公司 罗库溴铵粗品的精制方法
CN110240624B (zh) * 2019-08-01 2020-06-09 天津红日药业股份有限公司 一种雄甾烷衍生物及其制备方法与应用
CN111057122B (zh) * 2019-12-25 2021-04-30 武汉华龙生物制药有限公司 一种罗库溴铵的制备方法
CN112110880B (zh) * 2020-09-29 2022-09-09 天津红日药业股份有限公司 雄甾烷衍生物及其制备方法与应用
CN114088842B (zh) * 2021-11-19 2023-03-21 江苏正济药业股份有限公司 一种罗库溴铵中间体及杂质的检测方法

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GB1454749A (en) * 1972-11-29 1976-11-03 Akzo Nv 2beta, 16beta-diamino-androstanes and their preparation
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GB8709565D0 (en) * 1987-04-23 1987-05-28 Akzo Nv 2beta,16beta-diaminoandrostanes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7642246B2 (en) 2005-09-13 2010-01-05 Sicor Inc. Pure rocuronium bromide

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NL940010I1 (nl) 1994-07-18
ZA882481B (en) 1988-09-29
KR19980078895A (ko) 1998-11-25
IE63672B1 (en) 1995-05-31
FI89057C (fi) 1993-08-10
HUT47595A (en) 1989-03-28
DE3873803T2 (de) 1993-06-24
PT87250B (pt) 1992-08-31
ATE79631T1 (de) 1992-09-15
DK174743B1 (da) 2003-10-13
FI881707A0 (fi) 1988-04-13
JPS63277693A (ja) 1988-11-15
GB8708886D0 (en) 1987-05-20
ES2043781T3 (es) 1994-01-01
DK202888A (da) 1988-10-15
KR880012632A (ko) 1988-11-28
US4894369A (en) 1990-01-16
EP0287150A1 (fr) 1988-10-19
AU1457088A (en) 1988-10-20
AU608313B2 (en) 1991-03-28
DE3873803D1 (de) 1992-09-24
JPH0753751B2 (ja) 1995-06-07
GR3006275T3 (fr) 1993-06-21
DK202888D0 (da) 1988-04-13
KR0130208B1 (ko) 1998-04-03
NL940010I2 (nl) 1997-10-01
IE881017L (en) 1988-10-14
DE19575040I2 (de) 2003-09-18
PT87250A (pt) 1988-05-01
FI881707A (fi) 1988-10-15
CA1291117C (fr) 1991-10-22
HU198738B (en) 1989-11-28
FI89057B (fi) 1993-04-30
KR100221116B1 (ko) 1999-10-01
NZ224228A (en) 1990-03-27

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